Insular and limbic abnormal functional connectivity in early-stage Parkinson's disease patients with autonomic dysfunction.

Autonomic symptoms in Parkinson's disease result from variable involvement of the central and peripheral systems, but many aspects remain unclear. The analysis of functional connectivity has shown promising results in assessing the pathophysiology of Parkinson's disease. This study aims to investigate the association between autonomic symptoms and cortical functional connectivity in early Parkinson's disease patients using high-density EEG. 53 early Parkinson's disease patients (F/M 18/35) and 49 controls (F/M 20/29) were included. Autonomic symptoms were evaluated using the Scales for Outcomes in Parkinson's disease-Autonomic Dysfunction score. Data were recorded with a 64-channel EEG system. We analyzed cortical functional connectivity, based on weighted phase-lag index, in θ-α-ß-low-γ bands. A network-based statistic was used to perform linear regression between Scales for Outcomes in Parkinson's disease-Autonomic Dysfunction score and functional connectivity in Parkinson's disease patients. We observed a positive relation between the Scales for Outcomes in Parkinson's disease-Autonomic Dysfunction score and α-functional connectivity (network τ = 2.8, P = 0.038). Regions with higher degrees were insula and limbic lobe. Moreover, we found positive correlations between the mean connectivity of this network and the gastrointestinal, cardiovascular, and thermoregulatory domains of Scales for Outcomes in Parkinson's disease-Autonomic Dysfunction. Our results revealed abnormal functional connectivity in specific areas in Parkinson's disease patients with greater autonomic symptoms. Insula and limbic areas play a significant role in the regulation of the autonomic system. Increased functional connectivity in these regions might represent the central compensatory mechanism of peripheral autonomic dysfunction in Parkinson's disease.

Sudomotor and cardiovascular autonomic function in de novo Parkinson's disease assessed by sudoscan and cardiovascular reflexes.

OBJECTIVE: The prevalence of autonomic involvement in early stage of Parkinson 's disease (PD) is still debated. Aim of this study is to assess the autonomic functions in de novo PD patients (dnPD) in comparison with PD patients on therapy (PDot) and healthy controls (HC). METHODS: Twenty-eight dnPD and 24 PDot, to whom Unified Parkinson's Rating Scale (UPDRS) was administered, and 23 HC underwent electrochemical skin conductance (ESC) measured with sudoscan, cardiovascular reflexes (head-up tilt test HUTT, Valsalva maneuver, deep breathing, hand grip, and cold face),and Scales for Outcomes in Parkinson's Disease-Autonomic Dysfunction (SCOPA-AUT) questionnaire. RESULTS: The mean SCOPA-AUT total score was significantly higher in dnPD group compared with HC group (p < 0.001) and significantly lower than PDot (p = 0.004). No significant difference of ESC mean values were found between dnPD and HC group. DnPD had a significantly lower diastolic blood pressure (BP) response at handgrip test (p = 0.005) compared with HC. Hands and feet ESC significantly negatively correlated with disease duration (p = 0.014; p = 0.025) and feet ESC significantly negatively correlated with UPDRS III (p = 0.039). Systolic and diastolic BP responses at 3rd minute of HUTT correlated significantly negatively with disease duration (p < 0.001; p = 0.003) and with UPDRSIII (p = 0.001; p < 0.001). BP response to Valsalva maneuver negatively correlated with UPDRSIII (p = 0.006). CONCLUSION: Although dnPD patients complain of thermoregulatory symptoms, we found no alteration in the sudomotor function investigated with sudoscan. Furthermore, a deficit of the sympathetic vasoconstrictive response to the isometric exercise was detected, suggesting an early involvement of the autonomic cardiovascular components in dnPD.

Autonomic functions in focal epilepsy: A comparison between lacosamide and carbamazepine monotherapy.

OBJECTIVE: Some antiepileptic drugs (AEDs), like sodium channel blockers are significantly associated with autonomic dysfunction in patients with epilepsy. Unlike other sodium-blockers AEDs, lacosamide (LCM) is a third generation AEDs which enhances the slow inactivation of voltage-gated sodium channels. So far, data about LCM on autonomic nervous system are still unknown. This study was designed to investigate cardiovascular autonomic and sudomotor function in patients affected by focal epilepsy on LCM monotherapy, compared to patients treated with carbamazepine (CBZ) monotherapy and healthy subjects. METHODS: Patients on LCM underwent autonomic function tests including head up tilt test (HUTT), Valsalva maneuver, deep breathing, hand grip, and cold face. Heart rate variability (HRV) analysis was performed in rest condition and during HUTT. Sudomotor function was assessed through Sudoscan. All results were compared with patients on carbamazepine (CBZ) monotherapy and with healthy subjects. RESULTS: Fourteen patients on LCM monotherapy, 12 patients on CBZ monotherapy and 16 healthy controls were studied. At cardiovascular function tests, delta systolic blood pressure (∆SBP) at 3 min of HUTT and ∆SBP early phase II-late phase II at Valsalva maneuver were significantly lower in CBZ group compared to LCM patients. Spectral analysis of HRV showed no significant differences among LCM, CBZ and control groups. No difference in sudomotor function was found in all three groups. CONCLUSIONS: In conclusion, our findings suggest that LCM and CBZ on monotherapy do not affect autonomic cardiovascular and sudomotor functions compared to controls. Nevertheless, patients on CBZ showed a lower sympathetic reactivity with respect to LCM.

Autonomic symptoms, cardiovascular and sudomotor evaluation in de novo type 1 narcolepsy.

PURPOSE: To evaluate cardiovascular and sudomotor function during wakefulness and to assess autonomic symptoms in de novo patients with type 1 narcolepsy compared to healthy controls. METHODS: De novo patients with type 1 narcolepsy (NT1) and healthy controls underwent cardiovascular function tests including head-up tilt test, Valsalva maneuver, deep breathing, hand grip, and cold face, and sudomotor function was assessed through Sudoscan. Autonomic symptoms were investigated using the Scales for Outcomes in Parkinson's Disease-Autonomic Dysfunction (SCOPA-AUT) questionnaire. RESULTS: Twelve de novo patients with NT1 and 14 healthy controls were included. In supine rest condition and at 3 min and 10 min head-up tilt test, the systolic blood pressure values were significantly higher in the NT1 group than in controls (p < 0.05). A lower Valsalva ratio (p < 0.01), significantly smaller inspiratory-expiratory difference in deep breathing (p < 0.05), and lower delta heart rate in the cold face test (p < 0.01) were also observed in the NT1 group. The mean hand electrochemical skin conductance values were significantly lower (p < 0.05) and the mean SCOPA-AUT total scores were significantly higher in patients with NT1 than in healthy subjects (p < 0.001), with greater involvement of cardiovascular and thermoregulatory items. CONCLUSION: De novo patients with NT1 exhibit blunted parasympathetic activity during wakefulness, mild sudomotor dysfunction, and a large variety of autonomic symptoms.

Treatment with Dimethyl Fumarate Enhances Cholinergic Transmission in Multiple Sclerosis.

BACKGROUND: Dimethyl fumarate (DMF) exerts anti-inflammatory effects in multiple sclerosis by activating the Nrf2 antioxidant pathway, which is also stimulated by acetylcholine via alpha-7 nicotinic acetylcholine receptors. In animal models, Nrf2 potentiates cholinergic synaptic plasticity. OBJECTIVE: The aim of this study was to test whether treatment with DMF modulates cholinergic pathways in relapsing-remitting multiple sclerosis (RRMS). METHODS: Patients starting DMF (20) or IFN-ß 1a (20) and healthy subjects (20) were enrolled. Short-latency afferent inhibition (SAI), which is a transcranial stimulation measure of central cholinergic transmission, was recorded in patients and controls at baseline and, in patients only, after 6 months of treatment. Patients treated with DMF also underwent autonomic function testing to further explore peripheral and central cholinergic tone. RESULTS: At baseline, SAI was similar in patients and in controls (p = 0.983). Treatment with DMF significantly increased SAI (p = 0.01), while IFNß had no effect (p = 0.80). In the cold face test, DMF treatment also increased reflex bradycardia (p = 0.013), and reduced diastolic blood pressure variation (p = 0.010), further indicating its ability to stimulate cholinergic transmission. CONCLUSIONS: Treatment of MS patients with DMF results in increased cholinergic stimulation, with possible implications for neuroinflammation and neuroprotection.

Pisa Syndrome in Parkinson's Disease: Evidence for Bilateral Vestibulospinal Dysfunction.

INTRODUCTION: Pisa syndrome (PS) is a postural complication of Parkinson's disease (PD). Yet, its pathophysiology remains unclear, although a multifactorial component is probable. Cervical vestibular evoked myogenic potentials (cVEMPs) explore vestibulospinal pathway, but they have not been measured yet in PD patients with PS (PDPS) to assess a potential vestibular impairment. MATERIALS AND METHODS: We enrolled 15 PD patients, 15 PDPS patients, and 30 healthy controls (HCs). They underwent neurological examination and were examined with Unified Parkinson's Disease Rating Scale II-III (UPDRSII-III), audiovestibular workup, and cVEMP recordings. Data were analysed with Chi-square, one-way ANOVA, multinomial regression, nonparametric, and Spearman's tests. RESULTS: cVEMPs were significantly impaired in both PD and PDPS compared with HCs. PDPS exhibited more severe cVEMP abnormalities with prevalent bilateral loss of potentials, compared with the PD group, in which a prevalent unilateral loss was instead observed. No clinical-neurophysiological correlations emerged. CONCLUSIONS: Differently from HC, cVEMPs are altered in PD. Severity of cVEMPs alterations increases from PD without PS to PDPS, suggesting an involvement of vestibulospinal pathway in the pathophysiology of PS. Our results provide evidence for a significant impairment of cVEMPs in PDPS patients and encourage further studies to test validity of cVEMPs as diagnostic and prognostic biomarkers of PD progression.

Daytime autonomic activity in idiopathic rapid eye movement sleep behavior disorder: a preliminary study.

OJECTIVE: To investigate cardiovascular and sudomotor autonomic functions in patients with idiopathic rapid eye movement (REM) sleep behavior disorder (iRBD) during wakefulness compared to patients with Parkinson's disease (PD) and healthy subjects. METHODS: Drug-naïve iRBD patients, PD patients and healthy controls underwent cardiovascular function tests including head-up tilt test (HUTT), Valsalva maneuver, deep breathing, hand grip, and cold face. Heart rate variability (HRV) analysis was performed in the frequency domain using an autoregressive algorithm in the rest supine condition and during HUTT. Sudomotor function was assessed through Sudoscan. RESULTS: Fourteen iRBD patients, 17 PD patients and 12 healthy controls were included in the study. In the supine resting condition, the baseline values of systolic and diastolic blood pressure and heart rate were comparable in all groups. At Valsalva maneuver, iRBD patients and PD patients showed an overshoot which was significantly lower than controls. In addition, iRBD patients showed a significant reduction of sinus arrhythmia at deep breathing compared to controls. Cardiovascular responses to cold face were similar in the three groups while isometric handgrip was significantly reduced in PD patients with respect to healthy subjects. Spectral analysis of HRV showed no significant differences among iRBD, PD patients and controls in the supine resting condition; whereas during HUTT the low-frequency (LF) component of HRV was significantly higher in controls with respect to iRBD and the high-frequency (HF) component was significantly higher in iRBD patients compared to controls. In addition, a significant increase in the LF/HF ratio in healthy subjects was detected compared to iRBD. Finally, four out of 14 iRBD patients (29%) and nine of 17 PD patients (53%) had a sudomotor dysfunction. CONCLUSIONS: Our findings obtained in de novo iRBD and PD patients indicate that some alterations of the autonomic nervous system are shared by both groups of patients, reinforcing the close link between the two pathologies, and show an autonomic fragility during wakefulness in iRBD that mainly arises under stress conditions.

Does fatigue in Parkinson's disease correlate with autonomic nervous system dysfunction?

BACKGROUND: Despite its negative impact on quality of life, fatigue in Parkinson's disease (PD) remains an under-recognized issue and the underlying pathology is undetermined. OBJECTIVE: To contribute at understanding the pathogenesis of fatigue in a naturalistic cohort of cognitively intact PD patients. METHODS: In a Caucasian population of PD patients (n = 27), we evaluated to what extent fatigue (quantified as PFS-16 score) is associated with PD duration and with autonomic dysfunction, studied by both MIBG scintigraphy and autonomic nervous system testing. The latter included the head-up tilt test, Valsalva maneuver, deep breathing, and handgrip tests. RESULTS: PFS-16 score correlated with disease duration (R = 0.57, p = 0.002). Fatigue showed a clear correlation with deep breathing test (R = - 0.53, p = 0.004) but not with the MIBG H/M ratios. CONCLUSIONS: Our data are consistent with a multifactorial pathogenesis of fatigue and with effects of dopamine depletion in PD-related fatigue; on the other hand, our findings do not support a role for sympathetic denervation in PD-related fatigue.

Does continuous positive airway pressure treatment affect autonomic nervous system in patients with severe obstructive sleep apnea?

OBJECTIVE: This study is aimed at evaluating whether Continuous Positive Airway Pressure treatment (CPAP) may affect autonomic nervous system (ANS) in male patients with severe obstructive sleep apnea (OSAS). METHODS: We compared autonomic symptoms of de novo severe OSAS patients, OSAS patients on chronic CPAP treatment and healthy controls, using the Scales for Outcome in Parkinson disease-Autonomic (SCOPA-AUT) questionnaire. All groups underwent cardiovascular function tests including head-up tilt test (HUTT), Valsalva maneuver, deep breathing, hand grip and cold face tests. Statistical significance was set at p < 0.05. RESULTS: Twelve de novo severe OSAS patients, 17 male OSAS on CPAP and 14 controls were studied. The mean SCOPA-AUT total score was significantly higher in de novo OSAS patients compared with controls. Regarding the distinct domains, both de novo OSAS and CPAP group had abnormalities in respect of controls in urinary sphere. In supine rest condition the baseline values of systolic blood pressure were significantly increased in untreated OSAS patients compared with controls, whereas the basal values of diastolic blood pressure were significantly higher in CPAP patients with respect to controls. After ten min of HUTT, diastolic blood pressure changes were significantly higher in controls compared to both OSAS groups. Untreated OSAS patients showed significant different responses at deep breathing compared to controls. Both OSAS groups had a significant reduction of reflex bradycardia at cold face test. CONCLUSIONS: Our study shows that both treated and untreated OSAS patients complain of subjective autonomic symptoms like other sleep disorders reinforcing the close relationship between sleep and autonomic activity. Furthermore, cardiovascular reflexes indicate a tendency to hypertension and a reduced sensitivity to stimuli during wakefulness even in OSA patients on CPAP treatment, suggesting potentially permanent autonomic function deficits.

Heart rate variability is differentially altered in multiple sclerosis: implications for acute, worsening and progressive disability.

BACKGROUND: Sympathovagal imbalance has been associated with poor prognosis in chronic diseases, but there is conflicting evidence in multiple sclerosis. OBJECTIVES: The objective of this study was to investigate the autonomic nervous system dysfunction correlation with inflammation and progression in multiple sclerosis. METHODS: Heart rate variability was analysed in 120 multiple sclerosis patients and 60 healthy controls during supine rest and head-up tilt test; the normalised units of low frequency and high frequency power were considered to assess sympathetic and vagal components, respectively. Correlation analyses with clinical and radiological markers of disease activity and progression were performed. RESULTS: Sympathetic dysfunction was closely related to the progression of disability in multiple sclerosis: progressive patients showed altered heart rate variability with respect to healthy controls and relapsing-remitting patients, with higher rest low frequency power and lacking the expected low frequency power increase during the head-up tilt test. In relapsing-remitting patients, disease activity, even subclinical, was associated with lower rest low frequency power, whereas stable relapsing-remitting patients did not differ from healthy controls. Less sympathetic reactivity and higher low frequency power at rest were associated with incomplete recovery from relapse. CONCLUSIONS: Autonomic balance appears to be intimately linked with both the inflammatory activity of multiple sclerosis, which is featured by an overall hypoactivity of the sympathetic nervous system, and its compensatory plastic processes, which appear inefficient in case of worsening and progressive multiple sclerosis.

Chronic dopaminergic treatment in restless legs syndrome: does it affect the autonomic nervous system?

OBJECTIVE: The link between the autonomic nervous system and restless legs syndrome (RLS) has been recently postulated. Since dopaminergic agents are used as first-line treatment for RLS, the purpose of our study is to verify whether chronic pramipexole treatment could influence the autonomic control of cardiovascular reflexes and heart rate variability (HRV) in RLS during wakefulness. METHODS: Consecutive drug naive RLS patients underwent polysomnography (PSG), subjective scales, and cardiovascular function tests including head-up tilt test (HUTT), Valsalva maneuver, deep breathing, handgrip and cold face before and after 3-month pramipexole therapy. HRV analysis was performed in the frequency domain using both autoregressive and fast Fourier transform algorithms in rest supine condition and during HUTT. RESULTS: Twenty RLS patients reported a significant reduction of RLS symptoms after pramipexole treatment, while PSG did not show significant improvements except for periodic limb movement index. Pramipexole induced a trend to a lower systolic blood pressure and a significant higher variation of systolic and diastolic blood pressure at HUTT. Cardiovascular responses to the other tests were unchanged. No significant differences in HRV spectral analysis between drug naive and treated patients were observed. Moreover, the within-group analysis of HRV between orthostatic and supine position did not show any significant change in sympathetic and parasympathetic components both in the drug naive and pramipexole groups. CONCLUSIONS: Chronic pramipexole treatment does not seem to affect autonomic balance during wakefulness. Considering that neither PSG data nor autonomic parameters are significantly modified by pramipexole, we hypothesize a non-dopaminergic autonomic dysfunction in RLS.

Autonomic Function Tests and MIBG in Parkinson's Disease: Correlation to Disease Duration and Motor Symptoms.

AIMS: Disorders of the autonomic nervous system (ANS) have a variable degree of clinical relevance in patients with Parkinson's disease (PD). Here, we assessed whether subclinical autonomic dysfunction, as evaluated by a complete battery of autonomic function tests (AFTs), correlates with PD progression. METHODS: A series of 27 consecutive patients with PD underwent extensive ANS investigations including the head-up tilt test (HUTT), Valsalva maneuver, deep-breathing test, and handgrip test (HG); further, they performed 123I-meta-iodobenzylguanidine (MIBG) scintigraphy. RESULTS: Seven of the 27 patients showed orthostatic hypotension (OH) at HUTT and pathological responses to the deep-breathing and HG test and Valsalva maneuver. The majority of the remaining 20 patients with PD showed pathological responses to deep-breathing (n = 13) and/or HG (n = 11). Only 3 of 27 suffered relevant OH. MIBG uptake of myocardium was decreased in 19 patients with PD (H/M ratio 1.3 ± 0.2). Prolonged clinical observation (>3 years), persistent response to levodopa, and MIBG repetition allowed us to exclude negative MIBG as attributable to atypical Parkinsonism. MIBG uptake did not correlate with OH and other AFTs. Both HG test response and MIBG did correlate with the Unified Parkinson's Disease Rating Scale (UPDRS) motor score and disease duration. A positive correlation emerged between diastolic blood pressure (DBP) response to HG test and MIBG and with systolic blood pressure (SBP) response at tilt test. CONCLUSIONS: Our investigation suggests that ANS impairment affects the majority of patients with PD, even those PD patients showing negative MIBG, irrespective of clinical neurovegetative symptoms. The strict correlation that has been revealed with disease progression supports the routine utilization of AFTs as a reliable and inexpensive tool for monitoring peripheral sympathetic dysfunction in PD and optimizing therapy.

Is autonomic nervous system involved in restless legs syndrome during wakefulness?

OBJECTIVE: To investigate cardiovascular autonomic function in patients with restless leg syndrome (RLS) by means of cardiovascular reflexes and heart rate variability (HRV) during wakefulness. METHODS: Twelve RLS patients and 14 controls underwent cardiovascular function tests including head-up tilt test (HUTT), Valsalva maneuver, deep breathing, hand grip, and cold face. HRV analysis was performed in the frequency domain using both autoregressive (AR) and fast Fourier transform algorithms in rest supine condition and during HUTT. RESULTS: There was a significant increase in systolic blood pressure values in supine rest condition and a trend toward a lower Valsalva ratio in RLS patients with respect to controls. The significant and physiological changes of HRV at HUTT detected in healthy subjects were not found in RLS patients. CONCLUSION: RLS patients exhibit a tendency toward hypertension, reduced amplitude of both sympathetic and parasympathetic responses at HUTT, as well as blunted parasympathetic drive to blood pressure changes. These findings, if confirmed by more controlled studies, might support the hypothesis of autonomic nervous system involvement during wakefulness and consequently an enhanced cardiovascular risk in RLS.

The impact of rotigotine on cardiovascular autonomic function in early Parkinson's disease.

Dysautonomia can occur in early stages of Parkinson's disease (PD) influencing tolerance to dopaminergic therapies. Rotigotine, a non-ergot dopamine agonist, has recently been developed as an effective alternative antiparkinsonian drug, but its influence on the autonomic nervous system was not investigated. Twenty subjects out of 34 consecutive de novo PD patients were submitted to full assessment of cardiovascular autonomic function before and after reaching a stable rotigotine regimen [6 mg/24 h (n = 3) or 8 mg/24 h (n = 17)]. Patients reached significant clinical improvement (-27% on the Unified Parkinson's Disease Rating Scale part III) and did not show significant differences in cardiovascular tests compared to baseline data. However, an unexpected trend towards increasing systolic blood pressure after head-up tilt test was detected. Our study demonstrates that rotigotine does not influence cardiovascular autonomic responses in early de novo PD patients. Consequently, it may represent a well-tolerated and efficacious therapeutic option in newly diagnosed PD subjects.

Subclinical autonomic dysfunction in spinobulbar muscular atrophy (Kennedy disease).

INTRODUCTION: Spinobulbar muscular atrophy (SBMA) is an inherited adult-onset motor neuron disease caused by the expansion of a polyglutamine tract within the androgen receptor. Autonomic nervous system involvement (ANS) is not considered part of SBMA. The aim of this study was to assess autonomic cardiovascular function in 5 SBMA patients. METHODS: Five quantitative autonomic function tests (AFTs) were performed in 5 SBMA patients. Plasma noradrenaline (NA) concentration in patients and in 5 healthy subjects was also measured. RESULTS: AFTs were abnormal in 4 of the 5 patients, and plasma NA concentration was significantly reduced in patients with respect to controls. CONCLUSION: The impairment of cardiovascular responses to AFTs in addition to reduced plasma NA concentration observed in our patients suggests subclinical involvement of the ANS in Kennedy disease.

Percutaneous tibial nerve stimulation produces effects on brain activity: study on the modifications of the long latency somatosensory evoked potentials.

OBJECTIVE: Long-latency somatosensory evoked potentials (LL-SEP) provide information on the function of somatosensory cortical structures. Percutaneous tibial nerve stimulation (PTNS) is indicated in the treatment of lower urinary tract dysfunction. Aim of this study was to evaluate LL-SEP in patients with overactive bladder syndrome (OAB) treated by means of PTNS. METHODS: Sixteen female patients with a diagnosis of pharmacoresistant OAB underwent PTNS while eight female patients with the same diagnosis underwent sham stimulation. LL-SEP were performed at baseline and at the end of PTNS or sham stimulation. Peak latency and peak to peak amplitude of P80, P100, and P200 waves were measured. RESULTS: Mean latency of P80, P100, and P200 and mean amplitude of P200 did not show any significant change after both stimulation. Mean amplitude of P80 and P100 waves increased significantly after PTNS while it did not vary after sham stimulation. CONCLUSION: The P80 and P100 amplitude increase might reflect long-term modifications in synaptic efficiency through the somatosensory pathway. The plastic reorganization of cortical network triggered by peripheral neuromodulation can be hypothesized as a mechanism of action of PTNS. Further studies are needed to correlate LL-SEP modifications after PTNS with the success of the treatment.

Reversible postural tachycardia syndrome due to inadvertent overuse of Red Bull.

Postural tachycardia syndrome associated with a vasovagal reaction was recorded in a young volleyball player after an excess intake of Red Bull as a refreshing energy drink. Considering the widespread use of Red Bull among young people who are often unaware of the drink's drug content, this case report suggest Red Bull be considered a possible cause of orthostatic intolerance.